The present invention relates generally to hyperpolarized Helium-3 (xe2x80x9c3Hexe2x80x9d) and is particularly suitable for Magnetic Resonance Imaging (xe2x80x9cMRIxe2x80x9d) and NMR spectroscopic medical diagnostic applications.
Conventionally, MRI has been used to produce images by exciting the nuclei of hydrogen molecules (present in water protons) in the human body. However, it has recently been discovered that polarized noble gases can produce improved images of certain areas and regions of the body, which have heretofore produced less than satisfactory images in this modality. Polarized 3He and Xenon-129 (xe2x80x9c129Xexe2x80x9d) have been found to be particularly suited for this purpose. Unfortunately, as will be discussed further below, the polarized state of the gases are sensitive to handling and environmental conditions and, undesirably, can decay from the polarized state relatively quickly.
xe2x80x9cPolarizationxe2x80x9d or hyperpolarization of certain noble gas nuclei (such as 129Xe or 3He) over the natural or equilibrium levels, i.e., the Boltzmann polarization, is desirable because it enhances and increases MRI signal intensity, allowing physicians to obtain better images of the substance in the body. See U.S. Pat. No. 5,545,396 to Albert et al., the disclosure of which is hereby incorporated herein by reference as if recited in full herein.
For medical applications, after the hyperpolarized gas is produced, it is processed to form a non-toxic or sterile composition prior to introduction into a patient. Unfortunately, during and after collection, the hyperpolarized gas can deteriorate or decay (lose its hyperpolarized state) relatively quickly and therefore must be handled, collected, transported, and stored carefully. The xe2x80x9cT1xe2x80x9d decay constant associated with the hyperpolarized gas"" longitudinal relaxation time is often used to describe the length of time it takes a gas sample to depolarize in a given container. The handling of the hyperpolarized gas is critical, because of the sensitivity of the hyperpolarized state to environmental and handling factors and the potential for undesirable decay of the gas from its hyperpolarized state prior to the planned end use, i.e., delivery to a patient. Processing, transporting, and storing the hyperpolarized gasesxe2x80x94as well as delivery of the gas to the patient or end userxe2x80x94can expose the hyperpolarized gases to various relaxation mechanisms such as magnetic gradients, ambient and contact impurities, and the like.
In the past, various hyperpolarized delivery modes such as injection and inhalation have been proposed to introduce the hyperpolarized gas to a patient. Inhalation of the hyperpolarized gas is typically preferred for lung or respiratory type images. To target other regions, other delivery paths and techniques can be employed. However, because helium is much less soluble than xenon in conventional carrier fluids such as lipids or blood, 3He has been used almost exclusively to image the lungs rather than other target regions.
Recent developments have proposed overcoming the low solubility problem of helium by using a micro-bubble suspension. See Chawla et al., In vivo magnetic resonance vascular imaging using laser-polarized 3He microbubbles, 95 Proc. Natl. Acad. Sci. USA, pp. 10832-10835 (September 1998). Chawla et al. suggests using radiographic contrast agents as the injection fluid to deliver microbubbles of hyperpolarized 3He gas in an injectable formulation. This formulation can then be injected into a patient in order to image the vascular system of a patient.
Generally stated, one way currently used to load or produce the microbubble mixture is via xe2x80x9cpassivexe2x80x9d permeability. That is, the hyperpolarized 3He typically enters the walls of the micro-bubbles based on the helium permeability of the bubble itself. Thus, this gas loading method can take an undesirable amount of time, which can allow the hyperpolarized gas to decay unduly. Further, contact with the fluid or even the microbubble can result in contact-induced depolarization which can dominate the relaxation mechanisms of the hyperpolarized 3He and cause an undesirable reduction in the hyperpolarized life of the gas.
As such, there remains a need to improve micro-bubble 3He formulations and loading methods to minimize the decay of the polarized gas and improve the T1 of the micro-bubble formulation.
In addition, there is also a need to increase the ease of solubilizing hyperpolarized gaseous xenon, which, in the past, has been problematic.
It is therefore an object of the present invention to improve the T1 for a hyperpolarized 3He microbubble injectable solution.
It is another object of the present invention to reduce the effect of contact-induced depolarization to increase the hyperpolarized life of an injectable microbubble product.
It is an additional object of the present invention to produce an injectable microbubble solution in a way which increases the concentration of hyperpolarized 3He in the microbubbles in the injectable formulation.
It is another object of the invention to provide methods and devices for administering polarized microbubble injectable formulations to a subject in a manner which can rapidly mix and deliver the formulation to capitalize on the polarized state of the gas before it deleteriously decays.
It is another object of the present invention to process and form a hyperpolarized 3He gas mixture in improved containers and injection delivery systems which are configured to inhibit depolarization in the collected polarized gas.
It is yet another object of the invention to provide methods, surface materials and containers which will minimize the depolarizing effects of the hyperpolarized state of the 3He gas in a microbubble solution attributed to one or more of paramagnetic impurities, oxygen exposure, stray magnetic fields, and surface contact relaxation.
It is another object of the present invention to provide a dissolution assist method for facilitating the transition of hyperpolarized 129Xe from a gaseous to a liquid state.
These and other objects are satisfied by the present invention, which is directed to microbubble related hyperpolarized gas injectable solution (solubilized or liquid) products and related production and delivery methods, systems, and apparatus.
A first aspect of the present invention is directed to a method of producing an injectable formulation of hyperpolarized 3He. The method includes the steps of introducing a plurality of microbubbles into a chamber and then directing a quantity of hyperpolarized 3He into the chamber with the plurality of microbubbles. The pressure in the container is increased to above one atmosphere. A quantity of liquid is then directed into the chamber after the quantity of hyperpolarized gas and the microbubbles are located therein. The microbubbles with the (filled) hyperpolarized 3He contact the liquid thereby producing an injectable formulation of hyperpolarized 3He microbubbles.
In a preferred embodiment, the pressure is increased to above 2 atmospheres, and preferably increased to between about 2-10 atm. It is also preferred that the increasing step is performed after the microbubbles are introduced into the chamber and before the liquid is introduced therein.
Preferably, the liquid solution is selected such that it inhibits the depolarization of the gas based on contact with same. For example, in one embodiment, the fluid is selected such that it has low solubility values for 3He (preferably less than about 0.01, and more preferably less than about 0.005-0.008) or high diffusion coefficient value for 3He. In operation, the microbubble surface or walls are configured in the absence of the injection liquid to allow the hyperpolarized 3He to freely enter through the exterior cage-like shell of the bubble, then the fluid or liquid wraps around the openings in the cage-like shell to trap the hyperpolarized gas therein in such a way as to inhibit the transfer or leaching of the gas out of the microbubble. In addition, or alternatively, the fluid itself is introduced in a relatively limited quantity which can reduce the pressure differential between the 3He in the bubbles and those in the fluid and/or a quantity of 3He can be premixed with the liquid solution. The reduced pressure differential (saturation or equilibrium of the 3He in the fluid external of the bubbles) can reduce the amount of 3He which migrates therefrom.
In addition, even if the 3He exits the bubble, the low solubility of the selected fluid can reduce the amount of migration of helium from the bubble until equilibrium/saturation to prolong polarization associated therewith, thereby prolonging the T1 of the microbubble injectable mixture. Indeed, the selection of the fluid will be an important factor in establishing a sufficiently long T1 for the injectable formulation itself. Alternatively, or additionally, for formulations directed to 3He dissolved into liquid, it is preferred that the liquid have a high diffusion coefficient for 3He (high diffusion preferably meaning about 1.0xc3x9710xe2x88x925 cm2/s and more preferably at least 1.0xc3x9710xe2x88x924 cm2/s).
Another aspect of the present invention is directed toward a method of mixing and formulating polarized gaseous 3He for in vivo injection. The method includes the steps of introducing a quantity of microbubbles into a container and applying a vacuum to the container. The method also includes directing a first quantity of hyperpolarized 3He gas into the evacuated container with the microbubbles and directing a second quantity of a fluid into the container thereafter to form a bubble solution. The bubble solution is then removed from the container and injected into a subject.
Preferably, the second quantity of fluid comprises a substantially deoxygenated fluid and the injecting step includes delivering the bubble solution to an in situ positioned catheter inserted into the vein of a subject. It is also preferred that the mixing portion of the method be carried out temporally proximate to the injecting step (preferably performed within about 30 seconds prior to the injection).
An additional aspect of the present invention is directed toward a method of solubilizing gaseous hyperpolarized 129Xe. The method includes the steps of introducing a first quantity of bubbles into a chamber and directing a second quantity of hyperpolarized 129Xe into the chamber such that at least a portion of the 129Xe contacts the microbubbles. The method also includes the steps of dissolving a portion of the 129Xe and then separating substantially all of the microbubbles from the 129Xe prior to delivery of the dissolved phase of the 129Xe to a subject. The microbubbles act as an accelerant to solubilize the 129Xe from a gaseous state.
Yet another aspect of the present invention is a pharmaceutical injectable in vivo fluid hyperpolarized product. The product includes a first quantity of microbubbles formed from a first material and a second quantity of hyperpolarized 3He. The product also includes a third quantity of a liquid carrier solution. The third quantity is less than or substantially equal to the sum of the first and second quantities.
Preferably, the microbubbles are sized to be less than about 10 xcexcm in diameter and the injectable product is single bolus sized as about 50 cc""s.
The present invention includes methods to increase the density of the 3He in each microbubble (increasing the loading density) and to increase the bubble packing density to xe2x80x9cpackxe2x80x9d the bubbles more densely in the solution. Each can provide one or more of stronger signal strength and greater effective T1""s.
Further, the present invention can allow reduced bolus sized quantities of 3He. For example, venous hyperpolarized gas microbubble injection volumes of from about 5-50 cc""s, and more preferably about 15-30 cc""s, can provide sufficient signal for clinically useful images. Preferably, the microbubble formulations of the present invention are also formed such that the gas microbubbles are sized to be less than about 10 xcexcm and more preferably about 8 xcexcm or less in diameter so as to be able to be injected in a venous side of the circulation system and then pass through the capillaries to the arterial side of the circulation system
Advantageously, one or more of the loading of the gas into the bubble, and the delay in its escape, and the fluid packing and fluid compatibility can facilitate the delivery of quantities of the 3He in a manner which can allow the gas to be injected into a target area in a sufficient quantity and strength to provide clinically useful information.
The present invention, recognizing the very limited (T1) life of the microbubble formulations, also provides a rapid mixing and delivery device which can allow the bubble mixing and formulation preparation temporally proximate to the point of injection (preferably injected via a catheter). The present invention also allows for an NMR coil to be positioned on and/or operably associated with the microbubble formulation (on the gas-filled bubble formulation holding chamber or associated conduits, catheters, or holding chamber stems and the like) to allow for a polarization measurement to be conveniently obtained in conjunction with a planned delivery to better calibrate the signal intensity and/or reduce the delivery of depolarized substances.